1. Suppression of eIF2α kinases alleviates AD-related synaptic plasticity and spatial memory deficits
- Author
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Douglas R. Cavener, Eric Klann, Alyse J Wexler, Tao Ma, Clarisse Bourbon, Mimi A. Trinh, Evelina Gatti, and Philippe Pierre
- Subjects
Male ,Hippocampus ,Mice, Transgenic ,In Vitro Techniques ,Biology ,Presenilin ,Article ,Amyloid beta-Protein Precursor ,Mice ,eIF-2 Kinase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Alzheimer Disease ,Neuroplasticity ,Presenilin-1 ,medicine ,PSEN1 ,Animals ,Humans ,Maze Learning ,Anisomycin ,Aged ,030304 developmental biology ,Aged, 80 and over ,Protein Synthesis Inhibitors ,Memory Disorders ,0303 health sciences ,Neuronal Plasticity ,General Neuroscience ,Recognition, Psychology ,Long-term potentiation ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,chemistry ,Mutation ,Synaptic plasticity ,Female ,Alzheimer's disease ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Expression of long-lasting synaptic plasticity and long-term memory requires protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2 α-subunit (eIF2α). Elevated phosphorylation of eIF2α has been observed in the brains of Alzheimer's disease patients and Alzheimer's disease model mice. Therefore, we tested whether suppressing eIF2α kinases could alleviate synaptic plasticity and memory deficits in Alzheimer's disease model mice. Genetic deletion of eIF2α kinase PERK prevented enhanced phosphorylation of eIF2α and deficits in protein synthesis, synaptic plasticity and spatial memory in mice that express familial Alzheimer's disease-related mutations in APP and PSEN1. Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and defects in spatial memory exhibited by the Alzheimer's disease model mice. Our findings implicate aberrant eIF2α phosphorylation as a previously unidentified molecular mechanism underlying Alzheimer's disease-related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for treatment of individuals with Alzheimer's disease.
- Published
- 2013